Breast cancer is the most common type of cancer worldwide. Both men and women are susceptible to develop breast cancer, but the incidence of developing breast cancer is more common in women than in men. Worldwide, over 1.3 million women were diagnosed with breast cancer annually [1]. IARC reports a sharp increase in breast cancer incidence by 20% and mortality rate by 14% in 2012 compared with breast cancer incidence and mortality rate in 2008 [2]. Besides, the North American Association of Central Cancer Registries (NAACCR) reported that in 2013, breast cancer accounts for 29% of all new cancer cases in women and it is predicted to cause about 40,030 deaths in USA alone [3]. In Egypt, the National Cancer Institute (NCI) revealed that breast cancer is the most common cancer in women and accounts for 37.5% of all women cancers [4].
Chemotherapy either as a pre-operative therapy or a post-operative therapy is commonly used in the treatment of breast cancer. Basically, the main drawback of chemotherapeutics is their non-selective cytotoxic effect, which results in killing both cancer cells and normal cells, eventually causing severe adverse side effects such as bone marrow depression, neuropathy, nephropathy, GIT disorder, alopecia, etc. Doxorubicin (DOX) is the common chemotherapeutic agent used in clinic for the treatment of various cancers such as breast, lung and ovarian cancers. DOX, an anthracyline drug, possesses a potent anticancer action via inhibiting the topoisomerase-II-mediated DNA repair, intercalating with DNA, and causes DNA damage that eventually inducing cell apoptosis [5,6].
Despite its potent anticancer activity, DOX causes severe adverse side effects such as bone marrow depression, GI disorder, alopecia and cardiotoxicity. Cardiotoxicity is considered the main adverse side effect of DOX which limits its clinical use. DOX-medicated cardiotoxicity is dose-dependent since it was emphasized that the cumulative dose of DOX was the only confirmed risk factor for DOX-mediated cardiotoxicity. Beside the cardiotoxicity of doxorubicin, DOX has a short half-life, rapidly eliminated from the blood stream, resulting in low bioavailability of DOX at the tumor site. The low bioavailability of DOX provides only a partial treatment allowing some cancer cells to survive. These surviving cells mutate to prevent further DOX effect and being unresponsive to DOX; a phenomenon known as cancer resistance. Cancer resistance is a defense mechanism developed by cancer cells toward various chemotherapies such as DOX, and represents another obstacle limiting DOX clinical use. In fact, both resistance and systemic toxicity represent the main causes behind chemotherapy failure, which complicates cancer curability and leads to cancer progression [7-11].
Nanotechnology, a science of manipulating materials at the nano-scale, has received much attention across multiple disciplines as it offers novel and promising platforms suiting several industrial and biomedical applications. Nanotherapeutics is a targeted drug delivery system based on using nano-platforms (e.g. nanoparticles) as drug nano-carriers (NCs). These NCs such as NPs, have gained a great deal of attention in the biomedical field owing to their unique properties such as small sizes, large surface area, ease of surface modification, high stability and lower toxicity. All these unique NPs' properties offer a large drug loading capacity that permits drug loading to NPs via various strategies including drug encapsulation, physical drug loading over NPs' surfaces or covalent drug conjugation to NPs. Nanotherapeutics have provided desirable therapeutic characteristics over conventional therapy including prolonged systemic circulation lifetime, passive cancer targeting (selective killing of cancer cells) and nanoparticles-based combinatorial chemotherapy [12-14].
Nanotherapeutics provide a prolonged drug circulation half-life owing to the formulation of stealth NPs. Stealth NPs are considered a major breakthrough because of their ability to escape renal filtration, enzymatic degradation and the RES uptake and thus could circulate freely in the blood circulation [15, 12, 16]. Stealth NPs refer to NPs coated with polyethylene glycol (PEG), a synthetic hydrophilic polymer forming a hydration layer that sterically prevents biofouling, an accumulation of proteins and cells on the NPs surface, resulting in providing a prolonged drug systemic circulation half-life [13-14, 16-17]. Gabizon et al. conducted in-vivo studies to compare the pharmacokinetics between free doxorubicin and Doxil; DOX-loaded PEGylated-liposomes. It was found that the plasma concentration of Doxil was 300-fold higher than free doxorubicin in both human and animal studies. These studies confirmed that Doxil has an enhanced pharmacokinetics profile as compared to free doxorubicin [17]. Nanotherapeutics also provide a cancer targeted drug delivery system based on two mechanisms (i) passive targeting and (ii) active targeting. The passive targeting is based on NPs' small sizes and the enhanced permeability and retention (EPR) effect; a characteristic property of malignant tumors ascribed to their leaky blood vessels and poor lymphatic drainage. EPR effect is attributed to the improper angiogenesis developed by malignant tumor in order to obtain the required supplements to compensate its rapid proliferation. As a result, these leaky blood vessels are highly porous, allowing small and high molecular weight molecules such as NPs, which are a hundred times smaller than the red blood cells, to preferentially accumulate into the extracellular matrix of the tumor and become retained inside the cancer cells because tumor's vessels lack lymphatic drainage. Such a targeted drug delivery system increases the drug bioavailability at the tumor site and it also decreases the drug's adverse side effects. However, the conventional chemotherapy cannot take the advantage of EPR effect because the majority of chemotherapies have short half-lives. Consequently, these drugs are rapidly eliminated from the circulation by non-specific cellular and (RES) uptake as well as, enzymatic degradation before reaching the tumor site [5]. On the other hand, the active targeting mechanism depends on a discriminative property of cancer cells. Cancer cells exhibit an over-expression of specific receptors over their cell membranes that are not over-expressed by normal cells. Based on such a property, active targeting aimed at targeting these over-expressed receptors through employing a targeting or recognizing moiety such as antibodies or apatmers over the NCs' surfaces. This targeting moiety only recognizes and binds to its complementary receptor or protein, which is over-expressed over the surfaces of cancer cells. Such a targeting moiety delivers the anticancer agents to cancer cells specifically, leaving the neighboring normal cells untouched [16, 18]. Park et al. prepared Anti-human epidermal growth factor receptor2 (Anti-Her2)-conjugated liposomes and investigated their effects on HER-2 over-expressing breast cancer cells. It was reported that Anti-HER-2-conjugated liposomes demonstrated 700-fold higher cellular uptake compared to bare-liposomes [19]. Furthermore, the advent of nanotechnology permits the development of NPs-based combinatorial chemotherapy. These NPs-based combinatorial therapies enable co-delivery of multiple anticancer agents of different physiochemical properties using a single NC. Many clinically relevant reports stated that combinatorial chemotherapy became the main strategy to treat cancer particularly in the treatment of cancer chemo-resistance, as it promotes a synergistic anticancer action resulting in superior therapeutic efficacy when compared to single chemotherapy. Due to the aforementioned advantages, nanotherapeutics is considered an appealing approach for cancer therapy owing to its ability to improve chemotherapy's efficacy and pharmacokinetics profiles, which in turn results into minimizing the drug's dose and systemic toxicity.